rs61743088

Variant names:

• chr6-117394232-C-G
• rs61743088
• NM_001378902.1:c.1121G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-117394232-C-G
• chr6-117394232-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001378902.1(ROS1):​c.1121G>C​(p.Gly374Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00111 in 1,609,766 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (16 hom.)
• Consequence: ROS1 NM_001378902.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:2
• Conservation: PhyloP100: 4.97
• Publications: 9 publications found

Genes affected

ROS1 (HGNC:10261): (ROS proto-oncogene 1, receptor tyrosine kinase) This proto-oncogene, highly-expressed in a variety of tumor cell lines, belongs to the sevenless subfamily of tyrosine kinase insulin receptor genes. The protein encoded by this gene is a type I integral membrane protein with tyrosine kinase activity. The protein may function as a growth or differentiation factor receptor. [provided by RefSeq, Jul 2008]

ROS1 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000282218 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011647165).
• BS2: High Homozygotes in GnomAdExome4 at 16 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378902.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROS1	NM_001378902.1	MANE Select	c.1121G>C	p.Gly374Ala	missense	Exon 11 of 44	NP_001365831.1	Q5H8Y1
	ROS1	NM_002944.3		c.1094G>C	p.Gly365Ala	missense	Exon 10 of 43	NP_002935.2
	ROS1	NM_001378891.1		c.1121G>C	p.Gly374Ala	missense	Exon 11 of 44	NP_001365820.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ROS1	ENST00000368507.8	TSL:5 MANE Select	c.1121G>C	p.Gly374Ala	missense	Exon 11 of 44	ENSP00000357493.3	Q5H8Y1
	ROS1	ENST00000368508.7	TSL:1	c.1094G>C	p.Gly365Ala	missense	Exon 10 of 43	ENSP00000357494.3	P08922
	ENSG00000282218	ENST00000467125.1	TSL:2	c.548-72838G>C		intron	N/A	ENSP00000487717.1	A0A0J9YVX5

Frequencies

GnomAD3 genomes AF: 0.000809 AC: 123 AN: 152104 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00125

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00146 AC: 363 AN: 248022 AF XY: 0.00179

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000297

Gnomad ASJ exome AF: 0.000598

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000586

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.00114 AC: 1667 AN: 1457544 Hom.: 16 Cov.: 30 AF XY: 0.00144 AC XY: 1046 AN XY: 724978

African (AFR) AF: 0.000180 AC: 6 AN: 33262

American (AMR) AF: 0.000317 AC: 14 AN: 44126

Ashkenazi Jewish (ASJ) AF: 0.000269 AC: 7 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39456

South Asian (SAS) AF: 0.00928 AC: 793 AN: 85408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52978

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5756

European-Non Finnish (NFE) AF: 0.000669 AC: 743 AN: 1110250

Other (OTH) AF: 0.00139 AC: 84 AN: 60240

GnomAD4 genome AF: 0.000815 AC: 124 AN: 152222 Hom.: 1 Cov.: 32 AF XY: 0.000981 AC XY: 73 AN XY: 74420

African (AFR) AF: 0.0000963 AC: 4 AN: 41552

American (AMR) AF: 0.00124 AC: 19 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0104 AC: 50 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68002

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000572 Hom.: 0

Bravo AF: 0.000563

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00150 AC: 182

EpiCase AF: 0.000880

EpiControl AF: 0.000955

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Abnormal brain morphology (1)
-	-	1	not provided (1)
-	1	-	not specified (1)
-	-	1	ROS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.094	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.0
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.59
Sift	Benign	0.27	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.95	P
Vest4		0.27
MVP		0.65
MPC		0.21
ClinPred		0.67	D
GERP RS		5.1
Varity_R		0.23
gMVP		0.68
Mutation Taster		=92/8	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61743088; hg19: chr6-117715395;